Translocator protein

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Translocator protein (18kDa)
Identifiers
Symbols TSPO; BPBS; BZRP; DBI; IBP; MBR; PBR; PBS; PKBS; PTBR; mDRC; pk18
External IDs OMIM: 109610 MGI: 88222 HomoloGene: 574 ChEMBL: 5742 GeneCards: TSPO Gene
Orthologs
Species Human Mouse
Entrez 706 12257
Ensembl ENSG00000100300 ENSMUSG00000041736
UniProt P30536 P50637
RefSeq (mRNA) NM_000714 NM_009775
RefSeq (protein) NP_000705 NP_033905
Location (UCSC) Chr 22:
43.55 – 43.56 Mb		 Chr 15:
83.56 – 83.57 Mb
PubMed search [1] [2]
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Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It interacts with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain.[1] In humans, the translocator protein is encoded by the TSPO gene.[2][3] It belongs to family of tryptophan-rich sensory proteins.

Contents

Function [edit]

TSPO has many proposed functions,[4] the most studied of these are:

An indicator of the importance of TSPO is that disruption of the gene in mice results in embryonic death.[5]

Tissue distribution [edit]

Peripheral benzodiazepine receptors are found in many regions of the body including the human iris/ciliary-body.[7] Other tissues where peripheral benzodiazepine receptors are found include the heart, liver, adrenal and testis, as well as hemopoietic and lymphatic cells.[8] In lymphatic tissues, they modulate apoptosis of thymocytes via reduction of mitochondrial transmembrane potential.[9] PBRs have many other actions on immune cells including modulation of oxidative bursts by neutrophils and macrophages, and inhibition of macrophage secretion of cytokines inhibition of the proliferation of lymphoid cells and secretion of cytokines by macrophages.[10] "Peripheral" benzodiazepine receptors are also found in the brain, although only at around a quarter the expression levels of the "central" benzodiazepine receptors.[11]

Therapeutic Applications [edit]

TSPO has been shown to be involved in a number of processes such as inflammation,[12] and TSPO ligands may be useful anti-cancer drugs.[13][14] Activation of TSPO is also required for steroidogenesis to take place,[15][16] and this is particularly important for the production of neuroactive steroids such as allopregnanolone in the brain. This makes some TSPO ligands such as emapunil (XBD-173) useful as potential anxiolytics which may have less side effects than traditional benzodiazepine-type drugs.[17][18][19][20]

Imaging [edit]

Ligands of the TSPO are very useful for imaging of inflammation. For example, the radioligand [3H]-PK-11195 has been used in receptor autoradiography to study neuroinflammation following brain injury. The affinity of [11C]-PBR28 depends on a single polymorphism (rs6971) in the TSPO gene.[21]

Selective Ligands [edit]

Agonists [edit]

Peptides
  • Anthralin - 16kDa polypeptide, binds to both TSPO receptor and dihydropyridine-sensitive calcium channels with high affinity.[22]
  • Diazepam binding inhibitor (DBI) - 11kDa neuropeptide, potent agonist for TSPO receptor and stimulates steroidogenesis in vivo,[5][23][24] also negative allosteric modulator of benzodiazepine-sensitive GABAA receptors.[25]
  • DBI 17-50 fragment - active processing product of DBI
Non-peptides

Antagonists [edit]

  • PK-11195 - potent and selective antagonist for both rat and human forms of TSPO.
  • Ro5-4864 - original ligand with which TSPO receptor was characterised, now less used due to inter-species differences in binding affinity. Sedative yet also convulsant and anxiogenic in mice.[26]

PBR [edit]

In animals, the peripheral benzodiazepine receptor (PBR) is a mitochondrial protein (located in the outer mitochondrial membrane) characterised by its ability to bind a variety of benzodiazepine-like drugs, as well as to dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway. Depending upon the tissue, it was shown to be involved in:

The role of PBR in the regulation of cholesterol transport from the outer to the inner mitochondrial membrane, the rate-determining step in steroid biosynthesis, has been studied in detail. PBR is required for the binding, uptake and release, upon ligand activation, of the substrate cholesterol.[27] PBR forms a multimeric complex with the voltage-dependent anion channel (VDAC) [28] and adenine nucleotide carrier.[29] Molecular modeling of PBR suggested that it might function as a channel for cholesterol. Indeed, cholesterol uptake and transport by bacterial cells was induced upon PBR expression. Mutagenesis studies identified a cholesterol recognition/interaction motif (CRAC) in the cytoplasmic C terminus of PBR.[30][31]

In complementation experiments, rat PBR (pk18) protein functionally substitutes for its homologue TspO in R. sphaeroides, negatively affecting transcription of specific photosynthesis genes.[32] This suggests that PBR may function as an oxygen sensor, transducing an oxygen-triggered signal leading to an adaptive cellular response.

These observations suggest that fundamental aspects of this receptor and the downstream signal transduction pathway are conserved in bacteria and higher eukaryotic mitochondria. The alpha-3 subdivision of the purple bacteria is considered to be a likely source of the endosymbiont that ultimately gave rise to the mitochondrion. Therefore, it is possible that the mammalian PBR remains both evolutionarily and functionally related to the TspO of R. sphaeroides.

References [edit]

  1. ^ Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (August 2006). "Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function". Trends Pharmacol. Sci. 27 (8): 402–9. doi:10.1016/j.tips.2006.06.005. PMID 16822554. 
  2. ^ Chang YJ, McCabe RT, Rennert H, Budarf ML, Sayegh R, Emanuel BS, Skolnick P, Strauss JF (1992). "The human "peripheral-type" benzodiazepine receptor: regional mapping of the gene and characterization of the receptor expressed from cDNA". DNA Cell Biol. 11 (6): 471–80. doi:10.1089/dna.1992.11.471. PMID 1326278. 
  3. ^ Riond J, Mattei MG, Kaghad M, Dumont X, Guillemot JC, Le Fur G, Caput D, Ferrara P (January 1991). "Molecular cloning and chromosomal localization of a human peripheral-type benzodiazepine receptor". Eur. J. Biochem. 195 (2): 305–11. doi:10.1111/j.1432-1033.1991.tb15707.x. PMID 1847678. 
  4. ^ Casellas P, Galiegue S, Basile AS (2002). "Peripheral benzodiazepine receptors and mitochondrial function". Neurochem Int 40 (6): 475–86. doi:10.1016/S0197-0186(01)00118-8. PMID 11850104. 
  5. ^ a b c Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, Hardwick M, Li H, Vidic B, Brown AS, Reversa JL, Bernassau JM, Drieu K (January 1997). "Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis". Steroids 62 (1): 21–8. doi:10.1016/S0039-128X(96)00154-7. PMID 9029710. 
  6. ^ Frank W, Baar KM, Qudeimat E, Woriedh M, Alawady A, Ratnadewi D, Gremillon L, Grimm B, Reski R (September 2007). "A mitochondrial protein homologous to the mammalian peripheral-type benzodiazepine receptor is essential for stress adaptation in plants". Plant J. 51 (6): 1004–18. doi:10.1111/j.1365-313X.2007.03198.x. PMID 17651369. 
  7. ^ Valtier D, Malgouris C, Gilbert JC, Guicheney P, Uzan A, Gueremy C, Le Fur G, Saraux H, Meyer P (June 1987). "Binding sites for a peripheral type benzodiazepine antagonist ([3H]PK 11195) in human iris". Neuropharmacology 26 (6): 549–52. doi:10.1016/0028-3908(87)90146-8. PMID 3037422. 
  8. ^ Woods MG, Williams DC (1996). "Multiple forms and locations for the peripheral-type benzodiazepine receptor". Biochemical Pharmacology 52. pp. 1805–1814. doi:10.1016/S0006-2952(96)00558-8. PMID 8951338. 
  9. ^ Tanimoto Yutaka; Onishi, Yoshiaki (1999). "Benzodiazepine Receptor Agonists Modulate Thymocyte Apoptosis Through Reduction of the Mitochondrial Transmembrane Potential" (PDF). Jpn J Pharmacol. 79 (2): 177–183. doi:10.1254/jjp.79.177. PMID 10202853. 
  10. ^ Pawlikowski M (1993). "Immunomodulating effects of peripherally acting benzodiazepines". New York: In Peripheral Benzodiazepine Receptors. Academic press. pp. 125–135.  Unknown parameter |curly= ignored (help)
  11. ^ Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R (July 1982). "Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864". Molecular Pharmacology 22 (1): 26–32. PMID 6289073. 
  12. ^ Chen MK, Guilarte TR (April 2008). "Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair". Pharmacology & Therapeutics 118 (1): 1–17. doi:10.1016/j.pharmthera.2007.12.004. PMC 2453598. PMID 18374421. 
  13. ^ Santidrián AF, Cosialls AM, Coll-Mulet L, Iglesias-Serret D, de Frias M, González-Gironès DM, Campàs C, Domingo A, Pons G, Gil J (December 2007). "The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells". Haematologica 92 (12): 1631–8. doi:10.3324/haematol.11194. PMID 18055986. 
  14. ^ Kugler W, Veenman L, Shandalov Y, Leschiner S, Spanier I, Lakomek M, Gavish M (2008). "Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glioblastoma cells exposed to erucylphosphohomocholine". Cellular Oncology : the Official Journal of the International Society for Cellular Oncology 30 (5): 435–50. PMID 18791274. 
  15. ^ Veenman L, Papadopoulos V, Gavish M (2007). "Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response". Current Pharmaceutical Design 13 (23): 2385–405. doi:10.2174/138161207781368710. PMID 17692008. 
  16. ^ Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, Diaz G (August 2007). "Intracellular cholesterol changes induced by translocator protein (18 kDa) TSPO/PBR ligands". Neuropharmacology 53 (2): 318–29. doi:10.1016/j.neuropharm.2007.05.016. PMID 17631921. 
  17. ^ Mealy NE, Bayés M, Lupone B (2006). "Psychiatric Disorders". Drugs of the Future 31 (3): 259. 
  18. ^ Da Settimo F, Simorini F, Taliani S, La Motta C, Marini AM, Salerno S, Bellandi M, Novellino E, Greco G, Cosimelli B, Da Pozzo E, Costa B, Simola N, Morelli M, Martini C (September 2008). "Anxiolytic-like effects of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis". Journal of Medicinal Chemistry 51 (18): 5798–806. doi:10.1021/jm8003224. PMID 18729350. 
  19. ^ Taliani S, Da Settimo F, Da Pozzo E, Chelli B, Martini C (September 2009). "Translocator Protein Ligands as Promising Therapeutic Tools for Anxiety Disorders". Current Medicinal Chemistry 16 (26): 3359–80. doi:10.2174/092986709789057653. PMID 19548867. 
  20. ^ Rupprecht R, Rammes G, Eser D, Baghai TC, Schüle C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F, Uzunov V, McAllister KH, Bertaina-Anglade V, La Rochelle CD, Tuerck D, Floesser A, Kiese B, Schumacher M, Landgraf R, Holsboer F, Kucher K (June 2009). "Translocator Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like Side Effects". Science 325 (5939): 490–3. doi:10.1126/science.1175055. PMID 19541954. 
  21. ^ Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, Stjean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (October 2011). "An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28". J Cereb Blood Flow Metab 32 (1): 1–5. doi:10.1038/jcbfm.2011.147. PMC 3323305. PMID 22008728. 
  22. ^ Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A (December 1999). "Enigma of the peripheral benzodiazepine receptor". Pharmacological Reviews 51 (4): 629–50. PMID 10581326. 
  23. ^ Costa E, Auta J, Guidotti A, Korneyev A, Romeo E (June 1994). "The pharmacology of neurosteroidogenesis". The Journal of Steroid Biochemistry and Molecular Biology 49 (4–6): 385–9. doi:10.1016/0960-0760(94)90284-4. PMID 8043504. 
  24. ^ Garnier M, Boujrad N, Ogwuegbu SO, Hudson JR, Papadopoulos V (September 1994). "The polypeptide diazepam-binding inhibitor and a higher affinity mitochondrial peripheral-type benzodiazepine receptor sustain constitutive steroidogenesis in the R2C Leydig tumor cell line". The Journal of Biological Chemistry 269 (35): 22105–12. PMID 8071335. 
  25. ^ Bormann J, Ferrero P, Guidotti A, Costa E (1985). "Neuropeptide modulation of GABA receptor C1- channels". Regulatory Peptides. Supplement 4: 33–8. doi:10.1016/0167-0115(85)90215-0. PMID 2414820. 
  26. ^ Pellow S, File SE (July 1984). "Behavioural actions of Ro 5-4864: a peripheral-type benzodiazepine?". Life Sciences 35 (3): 229–40. doi:10.1016/0024-3205(84)90106-1. PMID 6087055. 
  27. ^ Papadopoulos V, Amri H, Li H, Yao Z, Brown RC, Vidic B, Culty M (2001). "Structure, function and regulation of the mitochondrial peripheral-type benzodiazepine receptor". Therapie 56 (5): 549–56. PMID 11806292. 
  28. ^ Garnier M, Dimchev AB, Boujrad N, Price JM, Musto NA, Papadopoulos V (February 1994). "In vitro reconstitution of a functional peripheral-type benzodiazepine receptor from mouse Leydig tumor cells". Mol. Pharmacol. 45 (2): 201–11. PMID 8114671. 
  29. ^ McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (April 1992). "Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier". Proc. Natl. Acad. Sci. U.S.A. 89 (8): 3170–4. doi:10.1073/pnas.89.8.3170. PMC 48827. PMID 1373486. 
  30. ^ Li H, Yao Z, Degenhardt B, Teper G, Papadopoulos V (January 2001). "Cholesterol binding at the cholesterol recognition/ interaction amino acid consensus (CRAC) of the peripheral-type benzodiazepine receptor and inhibition of steroidogenesis by an HIV TAT-CRAC peptide". Proc. Natl. Acad. Sci. U.S.A. 98 (3): 1267–72. doi:10.1073/pnas.031461598. PMC 14743. PMID 11158628. 
  31. ^ Papadopoulos V (January 2003). "Peripheral benzodiazepine receptor: structure and function in health and disease". Ann Pharm Fr 61 (1): 30–50. PMID 12589253. 
  32. ^ Yeliseev AA, Krueger KE, Kaplan S (May 1997). "A mammalian mitochondrial drug receptor functions as a bacterial "oxygen" sensor". Proc. Natl. Acad. Sci. U.S.A. 94 (10): 5101–6. doi:10.1073/pnas.94.10.5101. PMC 24638. PMID 9144197. 

External links [edit]

Mitochondrial proteins
Outer membrane
Intermembrane space
Inner membrane
Matrix
Other/to be sorted
Mitochondrial DNA
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